More than just vaccines

Tag Archives: immunization

When was the last time you made an important decision with 100% certainty?

Most, if not all, decisions in life come with risks, consequences or trade-offs. Healthcare is no different from anything else. Every surgery, pill, shot, even every new diet or exercise routine has its risks. And vaccines are not exempt. It’s true, vaccines have risks (probably the most common one for most vaccines is soreness at the injection site). And it’s no secret either—check out this list on the Center for Disease Control’s (CDC) website. They even list extremely rare reported events that they can’t prove were related to vaccination, but occurred around the same time.

Early recipients of vaccines understood side effects all too well. In the 1700’s, vaccination against smallpox, which entailed rubbing pus from an afflicted person into a small cut, was known to cause a mild form of disease, and in 1-2% of cases, death. But to those who saw what real smallpox could do firsthand, the risk was worth it, because even if they didn’t yet know how it worked, they knew that vaccination saved lives.

These days, vaccines are far safer, but the fear of potential side effects often overshadows the fear of disease. Perhaps the most notorious of these fears is the alleged and debunked link between autism and the measles, mumps and rubella (MMR) vaccine. Many researchers have taken an honest and thorough look at this and the question has been settled from a scientific standpoint.

As is the case with everything, though, people factor things besides scientific evidence into their decisions. For example, a sense of social responsibility may influence your decision to get the flu shot each year. You may also factor in anecdotes about a co-worker’s friend getting the flu after being vaccinated. Though rejecting one piece of information and blindly accepting another is everyone’s right, making an informed decision requires consideration of all types of information.

Many take the reasonable route of deferring to their doctors who have hopefully kept abreast of the scientific evidence and have likely seen the anecdotal evidence first hand. A doctor may defer to the recommendations of an organization like the Advisory Committee on Immunization Practices (ACIP), a rotating group of doctors and scientists who painstakingly study the science and side effects of every vaccine that goes onto the market. You can learn more about ACIP here and even attend their meetings if you want.

Then there are some who would like to have a couple of questions answered and to feel more involved and informed about their own, or their children’s health care. And then some who are just plain scared of the potential side effects. These lingering questions and fears surrounding vaccination are worth addressing (not to mention scientifically fascinating). For a thorough list of such questions, I recommend this site (and of course, it’s always wise to speak with a trusted healthcare professional about your concerns). Over the next couple of posts, I plan to explore some recent research that sheds light on a just couple of these questions:

First, can a vaccine make you sick? And second, why do vaccinated people still catch disease?

One way to explore the first question is look at the differences between the altered form of a virus found in a vaccine and the real deal. For something like the flu shot, which contains dead virus, the difference is obvious. If the virus is not alive, it can’t get into cells and replicate. It can, and should, activate immune cells, which could bring along soreness or a headache.

You may have heard about people getting the flu, or flu symptoms from the flu shot itself. There is some evidence that the act of getting the flu shot can put you at risk for the flu. One study published last year concluded that just going to the doctor slightly increased the probability of experiencing flu-like symptoms within the following two weeks (read this for more). If you get the vaccine at a clinic or doctor’s office, you could increase your chance of contact with people who have the flu or surfaces they have recently touched. It takes about a week for your body to generate antibodies good enough to protect you from the virus, so it’s definitely possible to get sick just after being vaccinated. For more flu myths, check out this list.

For some diseases, like measles, the immune system really needs to see a live vaccine to generate long-term immunity. The reason for this is not completely clear, but we do know that it takes a while for our bodies to generate the “best and brightest” long-lived immune cells and a dead vaccine may be cleared too quickly for this to happen. So, we’re stuck with live vaccines, at least until researchers come up with something better.

Do live vaccines have more risks than dead ones? Well, for some people, yes. There are a handful of case reports of kids with rare genetic immunodeficiency disorders getting polio from the vaccine, and live vaccines could make someone with uncontrolled AIDs sick. However, there have been very few reports of HIV+ people getting sick after receiving a live viral vaccine (Summarized here). And just to be safe, the CDC recommends pregnant women and those on immune-depleting chemotherapy avoid most live vaccines, though there is not a lot of data for or against them in those cases.

Lung cells fusing together into one, measles-infected “giant cell.”

But what about in the average healthy person? What happens after a live virus vaccine enters your body, and how is it different from a live, natural, infectious virus? Let’s take a closer look at the recently popular measles vaccine. The virus used in for measles vaccine is “weakened” because it’s been grown, harvested, and grown again and again in human or chicken cells in culture dishes. The virus adapted to its environment in a culture dish, and lost its potency in the human body. On a molecular scale, scientists are still collecting information about exactly how this “weakening” happens. One thing they know is that the vaccine version of the virus infects different kinds of cells than the natural version of the virus does.

One researcher working toward a better understanding of this question is W. Paul Duprex, at the Boston University School of Medicine. His lab engineered measles viruses to glow by giving them the gene for the jellyfish green fluorescent protein (GFP). Then they infected macaques monkeys with either the infectious natural measles virus or the vaccine strain and looked for the glowing viruses in different parts of the animals’ bodies. When they looked for the virus in blood or throat swabs, they found much less—orders of magnitudes less—of the vaccine strain compared to how much natural virus was growing in the monkeys. The researchers also examined slices of lymph nodes with a microscope and measured GFP in immune cells using a laser and detected very little, if any, of the vaccine virus strain inside immune cells. The infectious version, on the other hand, seemed to love infecting and dividing inside of immune cells.

Both viruses were able to infect one type of innate immune cell, but only in the lungs. And, it’s important to note that the scientists delivered both types of virus straight into the animals’ airways, so both strains had ample opportunity to infect. Just this month, though they published a study that mimicked the actual vaccine route, which is an injection into a muscle, and saw that the vaccine virus also only infected innate immune cells in the muscle. To see pictures of Duprex’s “glowing” virus infecting these cells, check out this recent National Geographic blog post.

When these innate immune cells, called dendritic cells and macrophages, get infected, they display little bits of the virus to other immune cells in nearby lymph nodes. For this reason, they are called professional antigen presenting cells. Other immune cells in the lymph nodes will generate a response, clear the present virus, and remember it well enough to prevent infection with the natural version in the future.

If innate immune cells brought the natural virus to the lymph nodes, cells in the lymph node would become infected and the virus would continue to spread throughout the body. This research is just getting started, but so far it looks like the vaccine version of the virus is well contained by dendritic cells and macrophages. They are professionals after all, and they do this kind of thing all day every day.

So, should you fear live viral vaccines? Well, do you fear the live bacteria, viruses and fungi living all over your body? Your immune system has done a good job at keeping them in check so far. If you’re generally healthy, a live viral vaccine is like a blip on your immune system’s radar.

I think of it like going on a roller coaster. You can stand in line and mull over all of the things that have a one in a million chances of going wrong, or consider the actual data–the hundreds of people who rode it without any incident just during the time you were in line.

In the case of live vaccines, millions of people have had them with no incident just in the past year. And unlike a roller coaster ride, the marginal risks of measles vaccination are exchanged for a major, life-long benefit.

Please note:

I am not a medical professional and the opinions within this blog are not intended to be used as medical advice.

This post is based on an article I recently wrote for an internship application, so it’s more formal than a typical post, but I think it’s a cool story that helps explain how the flu vaccine works. Enjoy! And stay healthy!

After more than 2,000 confirmed cases and over twenty deaths, the 2013-14 flu season is still approaching its peak. Vaccination remains the best prevention despite the flu vaccine’s hit-or-miss reputation. Each year the U.S. Food and Drug Administration recommends three strains of influenza that the World Health Organization believes are worth targeting, and six months later the season’s new vaccine is distributed.

This nasty viral particle is trying to get inside a cell. It’s covered in NA (red) and HA (blue) proteins.

One of the flu vaccine’s biggest problems is its inability to induce immunity against multiple viral subtypes. Subtypes of the influenza A virus, like H1N1 or H5N1 are distinguished by the surface proteins hemagglutinin (HA) and neuraminidase (NA). The vaccine can protect against a few subtypes at a time, but if a subtype not included in the shot makes a strong appearance one season, not much can be done to prevent it from spreading. This year, the vaccine is pretty spot on. It includes H1N1 which has been making a comeback this year.

This problem has driven researchers to pursue a universal vaccine that could protect against multiple subtypes. This type of protection is called heterotypic immunity. One group of scientists from St. Jude Children’s Research Hospital hit on an unexpected way to expand the reach of one flu vaccine to multiple subtypes. Dr. Maureen McGargill and her group published their study in Nature Immunology in December. They studied how a common immunosuppressive drug called rapamycin influenced the ability of vaccinated mice to generate heterotypic immunity. They vaccinated mice with one viral subtype and infected them with three other lethal subtypes. Surprisingly, the mice who got rapamycin were better able to resist infection by all the subtypes, including an altered H5N1 strain, commonly known as the avian flu.

Rapamycin is commonly used to dampen the immune system to prevent organ transplant rejection. It blocks an immune system regulating protein called mTOR. Three other animal vaccine studies previously found that rapamycin enhanced generation of memory T cells, cells that can remember a virus and kill infected cells when they detect viral proteins. None of these studies linked higher numbers of memory T cells to protection from infection. McGargill’s group observed both higher memory T cell numbers and better protection, but could not link the two. Rather, they found that protection was related to changes in the kinds of antibodies that the vaccine induced.

The flu vaccine contains pieces of viral proteins called antigens and mice and humans make antibodies that specifically bind these antigens on the viruses and neutralize them. The more specific the antibodies are though, the more they drive those proteins to mutate so the virus can escape detection. This shape-shifting tactic is called antigenic drift, and it is part of the reason it is so difficult to predict which vaccine formulation will be most effective each year.

The coveted universal vaccine would induce antibodies that recognize parts of the virus that are shared, or conserved, by many subtypes and unlikely to mutate. But B cells, the cells that make antibodies, tend to make more and more specific antibodies over time. Over several weeks, B cells go from making weak, broadly binding antibodies that can cross-react with many subtypes, to strong and specific ones. McGargill and her colleagues found that rapamycin interrupted this process and caused the mice to make more of the broadly binding antibodies. The antibodies also targeted different parts of the hemagglutinin protein.

The group could not determine exactly how the altered antibodies contributed to protection from infection. They concluded that the antibodies produced after rapamycin treatment were less specific and therefore able to cross-react with several viral subtypes. As a result, the treated mice were less susceptible to the three different influenza subtypes.

These findings could be useful for quickly designing broadly protective vaccines in the face of a new subtype outbreak or epidemic. It currently takes about six months to manufacture the annually recommended formulation. A heterotypic vaccine would not be as dependent on the World Health Organization’s laborious surveillance and data analysis, and could be stored and used for many flu seasons.

The other day I found myself in the break room near my lab eyeing a container of chocolate-covered nuts left over from the Christmas holiday. Someone left them out as a treat for foraging graduate students and post-docs. I stood for a moment holding a single piece in my fingers and as I was about to put it into my mouth, I remembered—Norovirus!

I had no reason to think the nuts could be a reservoir of norovirus, but I did have good reason to avoid shared uncooked food with an unknown history. A good chunk of my family had just had their holiday ruined by the virus, sometimes known as the 24-hour bug or stomach flu. It causes gastroenteritis, or inflammation of the gut, complete with diarrhea, vomiting and overall exhaustion. It can only be transmitted via stool or vomit, and though there was certainly none of that visible in the bin of delicious looking nuts, I began to think of all the hands that may have been inside. If it came from a family holiday party, some of those hands may have belonged to kids who haven’t yet learned to wash them for a full 30 seconds after using the bathroom. I threw the candy away, closed the container and left the break room.

I may have avoided norovirus that day by a judicious food choice, but not everyone has that moment of doubt before sharing a drink, holding a child’s hand or ordering a deli sandwich. It is sometimes just unavoidable, especially because it’s contagious for up to two weeks after the first horrible 24 hours. The center for disease control estimates that 19-21 million people are infected with norovirus each year and it’s actually responsible for somewhere between 600 and 800 deaths per year. Those most vulnerable are either over 65 or under 5 years old.

These figures are driving researchers to search for a vaccine, even if just for those most vulnerable or during outbreaks. But norovirus, or I should say noroviruses are particularly complicated. They are split into 5 groups (I-V) based on how similar their DNA sequences are. Those groups, called genogroups, are split into anywhere between 8 and 30 genotypes and those can be further divided into variants. The classification is complicated enough to require the use of a software program that compares genome sequences.

Only three of the genotypes can infect humans and the strain GII.4 has been the most common cause of outbreaks since the early 2000s. For decades before that, a different strain dominated, and the power structure may shift again. The abundance of genotypes and variants and their changing frequencies in communities make vaccine design a daunting task. On top of that, researchers are still discovering new genotypes and variants. In 2012 a strain called GII.4-Sydney was identified in Australia and made its way to the UK and the US within a year.

Up close scanning electron microscopic image of norovirus particles

There is evidence that infection with norovirus can generate immunity in some people, meaning that once they get infected, they are protected from re-infection for some weeks or months. However, no one knows how all of the viral subgroups and variants might affect immunity and vaccine design. In a study published in September, researchers from the University of Florida infected mice with one of two closely related norovirus strains and found major differences in the immune responses.

One of the two strains was much better at activating a class of immune cells called antigen presenting cells. These include dendritic cells and macrophages, and they are experts at displaying pieces of virus and training B and T cells to respond to the infection and turn into memory cells. As a result of the enhanced response, infected mice were protected from a reinfection six weeks later.

{Researchers determine “protection” by measuring how much virus shows up in an animal’s organs after infection. In this case, they measured norovirus in the small and large intestines and in the lymph nodes attached to the intestines.}

Oddly enough, the researchers narrowed down the cause of these changes down to a group of structural proteins whose sequences only varied by about 10% between the two strains.

A key finding in this study was that the protective norovirus strain protected mice from re-infection with both strains. This is important since any vaccine against norovirus would have to protect against several strains and genotypes. It also points out specific characteristics of the immune response that make all the difference between becoming immune or getting re-infected, for example, robust antigen presentation and B and T cell memory. A vaccine that could foster those characteristics could potentially protect people from several norovirus strains. It may take a while to get there. In the meantime I will keep my hands clean and out of community candy dishes.

*A reader noted that the poster above says norovirus is contagious for 2-3 days, whereas I wrote above that it can be contagious for 2 weeks. To clarify, the virus is most contagious for 2-3 days, but it can continue to be shed in stool for 2 weeks. See http://www.cdc.gov/norovirus/preventing-infection.html for more.

Signs outside of Walgreens and CVS have been advertising the flu vaccine for several weeks now. Even if its effectiveness varies from year to year, I consider it well worth the shot since I work around undergraduates and hospital personnel. Something I don’t expect to see this winter are advertisements for DTaP (diphtheria, tetanus, acellular pertussis) boosters even though they may be just as important for some as flu shots.

Pertussis, also called whooping cough, is caused by a lung infection with the bacterium Bordetella pertussis. It may sound like a nineteenth century disease you’d catch along the Oregon Trail, but whooping cough is a modern issue and can be serious or fatal, especially for newborns. According to Centers for Disease Control, the last few years have brought the largest pertussis outbreak since the 1950’s, reaching over 50,000 cases in 2012 (compared to a low of about 1000 in 1976). So, if we have a vaccine, why are there outbreaks?

In the 1950’s widespread use of the DTP vaccine (diphtheria, tetanus, pertussis) began in the U.S. In a couple of decades, the number of whooping cough cases dropped from about 50,000 to fewer than 1000. The vaccine was effective, but in the late 1970’s and then the 1980’s the vaccine’s side effects took center stage, perhaps as the memory of the disease faded. The DTP vaccine caused some combination of redness, swelling, pain and fever in about half of the children vaccinated. Some more serious reactions, like seizures were reported, but were transiently caused by fever and never led to permanent problems. Concerns that the vaccine caused neurological damage could not be substantiated and throughout the 1980’s, scientists reported that the risk of getting whooping cough outweighed the cost of the side effects.

From our point of view, it may seem brutal to accept such risks, but at the time, DTP was the only option available to prevent a disease that could be much more devastating. Whooping cough is named after the sound that infants make when they try (sometimes unsuccessfully) to take a breath in between coughing fits. The infection destroys structures in our lungs called cilia, which are tiny protrusions that collectively brush out grime from our lungs each day. They are like people in a mosh pit passing unwanted particulates out the door of your airway. When cilia are disabled, mucus collects in the lungs and your body copes by inducing spastic, uncontrollable coughs. Some can be extreme enough to slip vertebral discs or break ribs. The cough can last for months. For infants, the results are much worse because their lungs and airways are small so they have a much harder time catching their breath. This story gives an idea of how helpless parents and doctors can be to help an infant with pertussis.

Back to the 1980’s. Once the fear of the vaccine overcame fear of the disease, a new option had to be explored. The DTP contained whole bacteria that could not cause infection, but was causing inflammation in many vaccine recipients. Inflammation occurs when different types of immune cells gather in large numbers and release proteins that expand blood vessels and recruit more immune cells. Swelling follows and the cells release compounds that are meant to damage bacteria, but can also damage tissue. The process is usually well controlled and only lasts as long as it takes to remove whatever started it all off. The DTP vaccine, it turned out, caused inflammation because of a type of molecule called endotoxin in bacterial membranes. Endoxin non-specifically binds and activates immune cells and causes unchecked inflammation. So work began on a form of the vaccine with individual purified pieces of B. pertussis, called an acellular vaccine. It was approved as a booster by 1991 and the DTaP (diphtheria, tetanus and acellular pertussis) replaced the DTP completely by 1996.

It took about a decade to see the pattern emerge, but it’s starting to become clear that immunity after DTaP immunization does not last as long as immunity conferred by DTP. Since the vaccine requires 5 boosts, one potential cause could be under-immunization, or a failure to complete the whole vaccine course. A 2010 study reported that California kids who tested positive for pertussis were less likely to have received a fifth booster, which suggested that a full course was important for protection. But in the same study, many kids who did get the fifth boost were found in the infected group. These kids were also more likely to have received the last boost over a year prior to the study. That meant that even after five doses, the vaccine seems to wear off after a year. A more recent study done in Minnesota and Oregon also showed that kids’ susceptibility to getting pertussis increased a little more each year after the last booster.

So, under-immunization is not the whole story and although the DTaP vaccine works for about a year, there is something fundamentally different between it and DTP. It’s been suggested that it doesn’t cause enough inflammation or not the right kind of inflammation. So far, there is not enough basic science to support these ideas so researchers are taking a step back to ask simple questions about how the vaccine actually works (More on this in my next post).

Another idea is that B. pertussis is mutating and since DTaP only has a few of the bacteria’s proteins in it, dividing bacteria can start producing fewer or none of those proteins. This possibility is driving some scientists to explore different vaccine designs with more diverse proteins or to go back to a whole bacteria vaccine (like DTP), but without the super-inflammatory endotoxin. These explorations will depend on funding and it will take a long time to show that any new vaccine is effective, safe and cost-effective.

In the meantime, parents and doctors have to decide how best to use the existing vaccine to protect kids from whooping cough. Infants are the most vulnerable to the disease but they can’t be vaccinated for a couple of months after birth. Doctors and public health officials have turned to boosters for adolescents and adults with the idea that if parents and siblings are protected, they will be less likely to pass the infection to a newborn.

In 2005, the CDC recommended a 6th booster called Tdap for adolescents between 10 and 18 years old. One study tested the effectives of this method by comparing observed infection rates among infants to rates that were estimated based on data from previous years. They found that actual rates were significantly lower than the projected ones, bringing hope that cocooning may work. This year, Tdap boosting during pregnancy was deemed safe and was recommended by the CDC. Hopefully another year or two will bring evidence that vaccinating moms during each pregnancy reduces infant pertussis.

While researchers work on finding a happy medium between the inflammatory whole bacteria DTP and the fair-weather DTaP, we are left with rudimentary options: get Tdap boosters, keep kids up to date on their DTaP doses and wash your hands long enough to sing the “happy birthday” song three times.